Crystalline 21-deoxy-9alpha-fluoro 6alpha-methyl prednisolone



CRYSTALLINE 21-DEOXY-9oc-FLUORO 6oz-METHYL PREDNISOLONE JohnW. Shell,Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., acorporation of Delaware N Drawing. Filed May 21, 1959, Set. N0. 814,665

- 4 Claims. Cl. 167-58) This invention relates to a new polymorph andmore particularly relates to a new polymorph of21-desoxy-9afluoro-6-methylprednisolone.

2.1-desoxy-9u-fluoro-6-methylprednisolone is a recently developedcorticosteroid exhibiting marked specificity of anti-inflammatory actionon topical application. This specificity of topical action isdemonstrated by the high (i.e., 40 to 1)2l-desoxy-9a-fiuoro-6-methylprednisolone to hydrocortisone ratio oflocal anti-inflammatory activity as compared with the 1 to 121-desoxy-9oc-fluoro-6-methyl prednisolone to hydrocortisone ratio oforal activity. Because of the outstanding greater specific local overoral activity in the relatively small amount of this steroid requiredfor local eifect, 21-desoXy-9a-fluoro-6-methylprednisolone is unlikelyto cause undesirable systemic elfects due to possible absorption ofhormone following topical application.

Due to its outstanding therapeutic properties, the development of moreadvantageous forms of 2l-desoXy-9ufluoro-6-methylprednisolone to improvetherapeutic effectiveness is highly desirable.

It has now been discovered that this compound can 'be prepared in a newpolymorphic form (hereinafter 'des'- ignated as polymorph II). This newpolymorph is also unexpectedly more efiicacious when made up intotopical preparations than similar preparations madewith the oldpolymorph (hereinafter designated as polymorph I).

The polymorph of the present invention can be distinguished from the oldpolymorph by comparison of interplanar spacings as shown by thefollowing X-ray diffraction data:

INTERPLANAR SPACINGS, A.

Polymorph I Poly-morph II The foregoing X-ray data were obtained by thepowder Patented Apr. 4, 196 1 method using nickel filtered copper Karadiation. The

mg./ml. at 25 C.

21-desoxy-9a-fluoro-6-methylprednisolone "is an old H compound, themethod for the preparation of which is fully disclosed in US Patent No.2,867,637. However, the crystalline material disclosed in that patent isin the polymorphic form herein designated as I.

Illustratively, the polymorph of the present invention can bev preparedfrom polymorph I by dissolving the compound in an organic solvent whichwill provide a solution capable of boiling at the prevailing pressure ata temper ature in excess of about 280 C. and less than the decompositionmelting point of the steroid (i.e., 292 to 303 C.). Suitable organicsolvents include ethylene glycol or propylene glycol. The solutionshould be boiled almost to dryness and theresulting crystals collectedbefore the solution is completely dry to avoid thermal degradation.

Polymorph II may be formulated by usual pharmaceutical techniques fortherapeutic use. For example, the polymorph can be formulated intotablets, capsules, elixirs, syrups, ointments, powders, creams, lotions,eye drops, ear drops, pastes, jellies, injectable preparations, and thelike. It is, of course, most advantageously used in those dosage formswhere its greater topical specificity antifungal substances such asvioform, parabens, iodo-.

phors and the like; antipnuritics and local anesthetics such as camphor,menthol, benzocaine, calamine, and the like;

and tissue stimulants such as ichthammol, allantoin and the like.

The following examples are illustrative of the processes and products ofthis invention and are not to be construedaslimiting. a i V 74 ExampleOne gram of polymorph I of 21-desoxy-9a-fiuoro-6- methylprednisolone isdissolvedin 2 ml. of hot ethylene Y glycol. The solution is heated atatmospheric pressure 1 until most of the solvent is evaporated, and theresulting crystals are almost dry. The crystals are separated byfiltration, washed with petroleum ether, and are characterized by thefollowing X-ray dilfraction data:

INT ERPLANAR SPACINGS, A.

The thus-prepared polymorph II can be formulated by conventionaltechniques into a suitable topical ointment containing the followingingredients per gram:

200 mg. wool fat U.S.P.

544.25 mg. white petrolatum U.S.P.

250 mg. white mineral oil U.S.P.

5.5 mg. neomycin sulfate U.S.P., micronized 0.25 mg.21-desoxy-9u-fluoro-6methylprednisolone,

morph II Po y I 3 If antibiotic activity is not desired, neomycin can beINTERPLANAR SPACINGS, A. eliminated from the above formula. In eitherevent, 8 66 4 when applied by inunction twice a day to inflamed areas ofskin, the polymorph II containing ointment exhibits a high degree oftopical specificity :andettectiveness. The polymorph can also beformulated by conventional techniques into a suitable cream containingthe following ingredients per gram: 4 mg. n-butyl-p-hydroxybenzoate 1mg. methylparaben U.S.P. 160 mg. glyceryl monostearate 3. Apharmaceutical preparation comprising a topical 80 mg. spermaceti U.S.P.pharmaceutical carrier and from about 0.001 to about 5 0.25 mg.21-desoxy-9u-fluoro-6-methylprednisolone, polypercent21-desoxy-9a-fluoro-6a-methylprednisolone crysrnorph II talscharacterized by greater topical effectiveness and the 100 mg.polyethylene glycol 400 U.S.P. following X-ray diffraction data: addelcmzed Water INTERPLANAR SPACINGS, A.

When applied by inunction twice a day to inflamed areas 8.66 I 4.00 ofskin, the polymorph II containing cream exhibits a high 2 6.91 3.71degree of topical specificity and effectiveness. 6.30 3.52. It is to beunderstood that the invention is not to be 5.88 1 3.29 limited to theexact details of operation or exact composi- 5 .75 3.16 tions shown anddescribed herein as obvious modifications 5 .50 3.08 and equivalentswill be apparent to one skilled in the art, 25 -9 and the invention istherefore to be limited only by the 4-6 -91 scope of the appendedclaims. 4.31

l' ii 1S if 1s: 4. A cream for the treatment of topical anti-inflammanewcm of *3- tory disorders comprising a topically acceptable creamprednlsolone crystals characterlzed by increased solubility base and0025 percent 21 desoxy 9wfluomwmethyb water and the followmg Xraydlfiractlon data: prednisolone crystals characterized by greater topicaleffectiveness and the following X-ray diffraction data:

INTERPLANAR SPACINGS, A.

INTERPLANAR SPACINGS, A.

p armaceutica preparation comprising a pharmaceutical carrier and21-desoxy-9a-fluoro-6ot-methyl- References Cited m the file of thispatent UNITED STATES PATENTS prednisolone crystals characterized byincreased solubility in Water and the following X-ray diffraction data:2,867,637 Lincoln et al J an. 6, 1959

2. A PHARMACEUTICAL PREPARATION COMPRISING A PHARMACEUTICAL CARRIER AND21-DESOXY-9A-FLUORO-6A-METHYLPREDNISOLENE CRYSTALS CHARACTERIZED BYINCREASED SOLUBILITY IN WATER AND THE FOLLOWING X-RAY DIFFRACTION DATA:8.66 4.00 6.91 3.71 6.30 3.52 5.88 3.29 5.75 3.16 5.50 3.08 5.14 2.984.65 2.91 4.31